A5019110029- Hearing, Cochlea, Tinnitus, Genetics
- Hearing Loss and Rehabilitation
- Ion channel regulation and function
- Vestibular and auditory disorders
- RNA regulation and disease
- Biochemical Analysis and Sensing Techniques
- Neural dynamics and brain function
- Photoreceptor and optogenetics research
- Connexins and lens biology
- Neuroscience and Neuropharmacology Research
- Ion Channels and Receptors
- Cellular transport and secretion
- Neurogenesis and neuroplasticity mechanisms
- Neuroscience and Neural Engineering
- RNA and protein synthesis mechanisms
- Lipid Membrane Structure and Behavior
- Hereditary Neurological Disorders
- Mast cells and histamine
- Signaling Pathways in Disease
- Ear Surgery and Otitis Media
- Genetic Neurodegenerative Diseases
- Cell Adhesion Molecules Research
- Animal Vocal Communication and Behavior
- Congenital heart defects research
- Calcium signaling and nucleotide metabolism
University of Göttingen
2015-2025
Universitätsmedizin Göttingen
2016-2025
European Neuroscience Institute Göttingen
2019-2024
Universitätsklinik für Hals-, Nasen- und Ohrenheilkunde
2020
Max Planck Institute of Experimental Medicine
2019
Klinik und Poliklinik für Hals-Nasen-Ohren-Heilkunde
2018
Robert Koch Institute
2018
Harvard University
2007-2015
Massachusetts Eye and Ear Infirmary
2007-2015
University Medical Center
2014
Synaptic ribbons, found at the presynaptic membrane of sensory cells in both ear and eye, have been implicated vesicle-pool dynamics synaptic transmission. To elucidate ribbon function, we characterized response properties single auditory nerve fibers mice lacking Bassoon, a scaffolding protein involved anchoring ribbons to membrane. In bassoon mutants, immunohistochemistry showed that fewer than 3% hair cells' afferent synapses retained anchored ribbons. Auditory from mutants had normal...
Auditory prostheses can partially restore speech comprehension when hearing fails. Sound coding with current is based on electrical stimulation of auditory neurons and has limited frequency resolution due to broad spread within the cochlea. In contrast, optical be spatially confined, which may improve resolution. Here, we used animal models characterize optogenetic stimulation, genetically engineered express light-gated ion channel channelrhodopsin-2 (ChR2). Optogenetic spiral ganglion...
Inner hair cells (IHCs) of the cochlea use ribbon synapses to transmit auditory information faithfully spiral ganglion neurons (SGNs). In present study, we used genetic disruption presynaptic scaffold protein bassoon in mice manipulate morphology and function IHC synapse. Although partial-deletion mutants lacking functional (Bsn(ΔEx4/5)) had a near-complete loss ribbons from (up 88% ribbonless synapses), gene-trap (Bsn(gt)) showed weak residual expression 56% synapses, whereas remaining 44%...
Complexins (CPXs I–IV) presumably act as regulators of the SNARE (soluble <i>N</i>-ethylmaleimide-sensitive factor attachment protein receptor) complex, but their function in intact mammalian nervous system is not well established. Here, we explored role CPXs mouse auditory system. Hearing was impaired CPX I knock-out mice normal for II, III, IV, and III/IV measured by brainstem responses. were detectable cochlear hair cells expressed spiral ganglion neurons (SGNs) that give rise to nerve....
For sounds of a given frequency, spiral ganglion neurons (SGNs) with different thresholds and dynamic ranges collectively encode the wide range audible sound pressures. Heterogeneity synapses between inner hair cells (IHCs) SGNs is an attractive candidate mechanism for generating complementary neural codes covering entire range. Here, we quantified active zone (AZ) properties as function AZ position within mouse IHCs by combining patch clamp imaging presynaptic Ca(2+) influx...
We studied the role of synaptic ribbon for sound encoding at synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in mice lacking RIBEYE (RBEKO/KO). Electron immunofluorescence microscopy revealed a lack ribbons an assembly several small active zones (AZs) each contact. Spontaneous sound-evoked firing rates SGNs their compound action potential were reduced, indicating impaired transmission ribbonless IHC-SGN synapses. The temporal precision was recovery SGN-firing from...
Transgenic mice have become an important tool to elucidate the genetic foundation of human language faculty. While learning is essential prerequisite for acquisition speech, it still a matter debate whether auditory plays any role in development species-specific vocalizations mice. To study influence input on call development, we compared occurrence and structure ultrasonic from deaf otoferlin-knockout mice, model deafness DFNB9, those hearing wild-type heterozygous littermates.We found that...
Abstract The formation of central nervous system myelin by oligodendrocytes requires sterol synthesis and is associated with a significant enrichment cholesterol in the membrane. However, it unknown how concentrate above level found nonmyelin membranes. Here, we demonstrate critical role for proteolipids accumulation. Mice lacking most abundant protein, proteolipid protein (PLP), are fully myelinated, but PLP‐deficient exhibits reduced content. We therefore hypothesized that “high...
Abstract Myelinating oligodendrocytes enable fast propagation of action potentials along the ensheathed axons. In addition, play diverse non-canonical roles including axonal metabolic support and activity-dependent myelination. An open question remains whether myelination also contributes to information processing in addition speeding up conduction velocity. Here, we analyze role myelin auditory using paradigms that are good predictors speech understanding humans. We compare mice with...
EF-hand Ca(2+)-binding proteins are thought to shape the spatiotemporal properties of cellular Ca(2+) signaling and prominently expressed in sensory hair cells ear. Here, we combined genetic disruption parvalbumin-α, calbindin-D28k, calretinin mice with patch-clamp recording, vivo physiology, mathematical modeling study their role signaling, exocytosis, sound encoding at synapses inner (IHCs). IHCs lacking all three showed excessive exocytosis during prolonged depolarizations, despite...
Saltatory electric conduction requires clustered voltage-gated sodium channels (VGSCs) at axon initial segments (AIS) and nodes of Ranvier (NR). A dense membrane undercoat is present these sites, which thought to be key for the focal accumulation channels. Here, we prove that βIVΣ1 spectrin, only βIV spectrin with an actin-binding domain, essential component this coat. Specifically, coexists βIVΣ6 both AIS NR, being predominant AIS. Removal alone causes disappearance nodal coat, increased...
How size and shape of presynaptic active zones are regulated at the molecular level has remained elusive. Here we provide insight from studying rod photoreceptor ribbon-type after disruption CAST/ERC2, one cytomatrix zone (CAZ) proteins. Rod photoreceptors were present in normal numbers, a-wave electroretinogram (ERG)--reflecting their physiological population response--was unchanged CAST knock-out (CAST(-/-)) mice. Using immunofluorescence electron microscopy, found that zones, Ca(2+)...
Although there are nearly 100 different causative genes identified for nonsyndromic hearing loss (NSHL), Sanger sequencing-based DNA diagnostics usually only analyses three, namely, GJB2, SLC26A4, and OTOF. As this is seen as inadequate, a need high-throughput diagnostic methods to detect disease-causing variations, including single-nucleotide variations (SNVs), insertions/deletions (Indels), copy-number (CNVs). In study, targeted resequencing panel was developed 79 NSHL selected forms of...
Ca(2+) influx triggers the fusion of synaptic vesicles at presynaptic active zone (AZ). Here we demonstrate a role Ras-related in brain 3 (Rab3)-interacting molecules 2α and β (RIM2α RIM2β) clustering voltage-gated CaV1.3 channels AZs sensory inner hair cells (IHCs). We show that IHCs hearing mice express mainly RIM2α, but also RIM2β RIM3γ, which all localize to AZs, as shown by immunofluorescence microscopy. Immunohistochemistry, patch-clamp, fluctuation analysis, confocal imaging...
Nature Communications 8: Article number: 14530 (2017); Published 21 February 2017; Updated March 2017 The financial support for this was not fully acknowledged. Acknowledgements should have included the following: research funded by a grant from Medical Research Council (MR/N004299/1) and German Foundation (DFG) through priority programme 1608.
Hearing impairment is the most common sensory disorder in humans. So far, rehabilitation of profoundly deaf subjects relies on direct stimulation auditory nerve through cochlear implants. However, some forms genetic hearing impairment, organ Corti structurally intact and therapeutic replacement mutated gene could potentially restore near natural hearing. In case defects otoferlin ( OTOF ), such therapy hindered by size coding sequence (~6 kb) exceeding cargo capacity (&lt;5 preferred...
Cysteine string protein (CSP) α is an abundant synaptic vesicle that contains a DNA-J domain characteristic of Hsp40-type cochaperones. Previous studies showed deletion CSPα in mice leads to massive lethal neurodegeneration but did not clarify how the affects specific subpopulations neurons. Here, we analyzed effects deficiency on tonically active ribbon synapses retina and inner ear. We show CSPα-deficient photoreceptor terminals undergo dramatic rapidly progressive starts before eye...
Hearing relies on Ca 2+ influx-triggered exocytosis in cochlear inner hair cells (IHCs). Here we studied the role of channel subunit V β 2 hearing. Of 1–4 mRNAs, IHCs predominantly contained . was severely impaired mice lacking extracardiac tissues ( −/− ). This involved deficits amplification and sound encoding. Otoacoustic emissions were reduced or absent mice, which showed strongly elevated auditory thresholds single neuron recordings brainstem response measurements. greatly (by 68%)....